The present invention provides a tablet with optimal mechanical strength, which when placed in the oral cavity rapidly dissolves or disintegrates without water, preferably within about 60 seconds.
More particularly, the present invention relates to composite excipients produced by substantially completely coating calcium silicate with a carbohydrate, and the use of these composite excipients in orally disintegrating tablets.
Design of an orally disintegrating tablet requires a significant amount of research work in order to develop a process that maintains enough porosity inside the compressed tablets for fast dissolving or fast melting while maintaining the mechanical strength of the tablet. Orally disintegrating dosage forms are known in the art and some of the most commonly used techniques are incorporated herein by reference Current technologies involved in many patents as well as existing commercial fast-dissolving tablets utilize complicated processing techniques such as freeze-drying, molding and sublimation or use of specialized excipients such as effervescent couple, highly micronized agents or the likes.
Freeze drying is one common process for producing many commercial fast dissolving tablets wherein a cake or wafer is prepared by freeze drying a solution or suspension of the medicament and suitable excipients in water or other solvents. Such systems dissolve very rapidly on the tongue, due to their high affinity for moisture and a very high porosity. U.S. Pat. No. 5,298,261 discloses freeze-drying a slurry or paste comprising an active ingredient and excipients placed in blister packets. PCT application WO 97/36879 discloses vacuum drying, at room temperature or a slightly elevated temperature, of a suspension including the active drug, a sugar alcohol, PEG 6000, talc, sweeteners and flavors, in preformed blisters. However, the freeze-drying process suffers from several disadvantages. The primary disadvantage is that solutions employed for freeze-drying are aqueous and, therefore, not suited for water sensitive medicaments. Freeze-drying is also limited to low dose actives. The process itself is typically laborious, costly and time-consuming. Finally, the resultant dosage forms, in addition to being hygroscopic, tend to be very soft, and therefore require special moisture-resistant and impact-resistant packaging and careful handling.
U.S. Pat. No. 5,464,632 claims the use of high levels of disintegrants, such as 16% starch 1500 and 13.3% crospovidone, for a disintegration time of 35 seconds to 45 seconds. However, such tablets have a chalky or dry feel when placed in the mouth.
U.S. Pat. No. 5,178,878 discloses a rapidly dissolving oral formulation that requires an extragranular microparticulate active in conjunction with an effervescent agent incorporated into a tableted matrix in order to achieve rapid oral disintegration. Many fast-dissolving tablets are also formulated by the inclusion of effervescent compounds. U.S. Pat. No. 5,178,878 and WO 91/04757 disclose the addition of an effervescent couple (such as sodium bicarbonate and citric acid) to a tablet. Exposure of such tablet to moisture results in contact and chemical reaction between the effervescent couple which leads to gas production and tablet disintegration. However, tablets which include effervescent pairs are highly sensitive to moisture and require a specific, very costly plant including special handling equipment, controlled-humidity environments, as well as special moisture resistant packaging. Such preparations have an unpleasant mouth feel.
Another orally disintegrating technique is spray drying technology as explained in U.S. Pat. Nos. 5,958,471 and 6,165,511, which includes preparing an aqueous solution of more than 80% of one or more non-hygroscopic polyols, and spraying the resulting mixture into an air stream. The resulting composition of the spray-drying process contains a filamentous structure. Similarly PCT application WO 03/051338A1 relates to a method for producing a directly compressible and highly compactible composition by co-spray drying of mannitol and sorbitol solution resulting in nonfilamentous microstructure. Both these patents describe use of highly concentrated aqueous solutions, which are to be maintained and sprayed at high temperature, thus demanding special equipment.
Another approach to develop orally disintegrating dosage form involves optimal selection of excipients which would result in desired disintegration time. These are typically compressed dosage forms. EP 1145711 describes the preparation of flash-melt dosage forms that disintegrate in the mouth in less than 25 second. They consist of granules composed of a superdisintegrant (4-8%), a dispersing agent such as calcium silicate (20-70%), a distributing agent selected from amorphous silica, fumed silica, diatomaceous earth, talc, kaolin, magnesium aluminum trisilicate, and a binder (10 to 50% by weight). Although a larger amount of binder may produce stronger tablets, the disintegration times tend to increase. To counter this, a large amount of dispersing and distributing agent is included in the formulation which increases the weight of the tablet. This may increase the cost of the formulation.
PCT application WO 03/045844A1 relates to synthetic calcium metasilicate, which when incorporated in a solid product, significantly increases the disintegration rate of the formed product when contacted by a substantially aqueous environment. The reduction in disintegration time with calcium silicate is more pronounced with immediate release tablets, as tablets prepared with calcium silicate have lower porosity. Further, the use of calcium silicate with conventional equipments leads to discoloration of the final dosage form due to interaction of calcium silicate with some metals, as well as reaction with many active pharmaceutical agents (hereinafter the “API”.) Calcium silicate, due to its hydrophobic and static nature, results in blends with very poor flow properties causing weight and content variation during compression into tablets. Further, it also imparts a chalky taste to the dosage form.
In general, there are numerous other examples of specific formulations that utilize one or more of the techniques or mechanisms discussed above. Majority of these techniques possess one or more of the above enumerated disadvantages to some extent such as tedious and complex method of manufacturing, special packaging and storage requirements, high cost, limitation on drug load etc. Thus, there continues to be a need for a formulation that mitigates or eliminates these disadvantages. The desired features of such dosage form include quick disintegrability in an oral cavity, a pleasant mouth feel and optimal mechanical strength even in storage under a humidifying conditions.
It was surprisingly found that composite excipients made by co-processing of at least one water soluble excipient and at least one water insoluble excipient such as calcium silicate, leads to a formulation that rapidly disintegrates or dissolves on in the mouth. More specifically, it has been discovered that a composite excipient formed by substantially completely coating the calcium silicate in a carbohydrate, the calcium silicate is prevented from reacting with the API or processing equipment, and further exhibits greatly improved flow properties.
Tablets made with this improved composite excipient exhibit low friability, low ejection forces and hardness sufficient to be processed in high speed tableting machines and shipped in low cost packages, while retaining rapid disintegration or dissolution properties. The tablets have a pleasant mouth feel and good mechanical strength such that they do not require special handling or packaging conditions.